The immunotherapy of patients with cancer requires the generation in vivo of large numbers of highly avid anti-tumor lymphocytes that can overcome normal tolerance and sustain an attack against a solid tumor. Immunization of melanoma patients with cancer antigens can increase the number of circulating CD8+ cytotoxic T-lymphocyte precursor cells (pCTL), but this has not correlated with clinical tumor regression, suggesting a defect in function or activation of the pCTL (Rosenberg et al., Nat. Med 4: 321 (1998)).
Adoptive cell transfer therapy provides the opportunity to overcome tolerogenic mechanisms by enabling the selection and ex vivo activation of highly selected T-cell subpopulations and by manipulating the host environment into which the T-cells are introduced. Prior clinical trials, including the transfer of highly active cloned anti-tumor T-cells failed to demonstrate engraftment and persistence of the transferred cells (Rosenberg et al., J. Nat'l. Cancer Inst. 86(15): 1159 (1994); Yee et al., J. Exp. Med. 192: 1637 (2000); Dudley et al., J. Immunother. 24(4): 363 (2001); Dudley et al., J. Immunother. 25(3): 243 (2002)). Lymphodepletion can have a marked effect on the efficacy of T-cell transfer therapy in murine models (Berenson et al., J. Immunol. 115: 234 (1975); Eberlein et al., J. Exp. Med. 156: 385 (1982); North, J. Exp. Med. 155: 1063 (1982); and Rosenberg et al., Science 233: 1318 (1986)) and may depend on the destruction of suppressor cells, disruption of homeostatic T-cell regulation, or abrogation of other normal tolerogenic mechanisms.
The present invention seeks to overcome the deficiencies in the art by providing a combined method of nonmyeloablative lymphodepleting chemotherapy and immunotherapy in which the transferred cells engraft and persist and promote the regression of a cancer. This and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the detailed description provided herein. 